Abstract
Cell death receptors have crucial roles in the regulation of immune responses. Here we review recent in vivo data confirming that the Fas death receptor (TNFSR6) on B cells is important for the regulation of autoimmunity since the impairment of only Fas function on B cells results in uncontrolled autoantibody production and autoimmunity. Fas plays a role in the elimination of the non-specific and autoreactive B cells in germinal center, while during the selection of antigen-specific B cells different escape signals ensure the resistance to Fas-mediated apoptosis. Antigen-specific survival such as BCR or MHCII signal or coreceptors (CD19) cooperating with BCR inhibits the formation of death inducing signaling complex. Antigen-specific survival can be reinforced by antigen-independent signals of IL-4 or CD40 overproducing the anti-apoptotic members of the Bcl-2 family proteins.
Highlights
Apoptosis may be mediated by intrinsic or extrinsic mechanisms
We summarize the different survival signals protecting activated B cells from Fas-induced cell death
Results observed in B cell specific FLIP-deficient mice indicate that FLIP is dispensable for the development of B cells in the bone marrow
Summary
Different stimuli such as irradiation, drugs, cytokine deprivation, DNA damage, anoikis, ER stress, etc., lead to the permeabilization of the mitochondrial membrane, activating the intrinsic pathway This intrinsic pathway is mainly regulated by the balance and interaction of the pro- and anti-apoptotic proteins of the Bcl-2 family. Pro and pre-B cells as non-activated lymphocytes die principally by intrinsic pathways, through the upregulation of the Bim pro-apoptotic factor In these stages of cell development, different survival signals, such as IL7 or BCR tonic signals trigger elevated levels of A1 or Mcl-1 anti-apoptotic proteins of the Bcl-2 family (Opferman, 2008). Upon antigen recognition, immunoreceptor triggering, cytokines or growth factors (mainly through the regulation of AKT; Suzuki et al, 2003), the Jak-STAT (Khaled and Durum, 2003) pathway, and elevated metabolism (Khan, 2009) strongly push the balance of pro- versus anti-apoptotic members www.frontiersin.org
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